Ocular drug dispensing system

ABSTRACT

An ocular drug dispensin device for administering a drug at a controlled and continuous dosage unit rate to the eye to produce a local or systemic physiological or pharmacological effect is comprised of a shaped body insoluble in tear fluid and comprised of a first wall, a third wall distant from the first wall, a second wall interposed between the first and third wall and extending around their peripheries for sealingly engaging the first and third wall, a reservoir defined by the inner surfaces of the walls and containing the drug or a mixture of the drug in a carrier and wherein at least one of the first and third walls is formed of an imperforate drug release rate controlling material permeable to the passage of drug or a microporous material containing in the micropores a drug release rate controlling medium permeable to the passage of drug for administering a therapeutically effective amount of drug over a prolonged period of time.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 493,819 filed on Aug. 1, 1974 which application is acontinuation of U.S. patent application Ser. 2,227,051 filed on Feb. 17,1972, all now abandoned. These applications are assigned to the sameassignee of this application and benefit of their filing dates isclaimed.

BACKGROUND OF THE INVENTION

This invention relates to an ocular drug dispensing device foradministering a drug to the eye at a controlled and continuous dosagerate.

One of the first ocular devices for dispensing drugs directly to the eyeconsisted of a lamella of a drug dissolved or dispersed in awater-soluble gel of glycerinated gelatin that was applied to the innersurface of the eyelid. The glycerinated gelatin dissolved rapidly intear fluid with an accompanying quick release of drug to produce thesame kind of effect as liquid dosage forms such as eye drops orointments. Such lamellae do not provide sustained dispensing and theyare not generally used in ophthalmic therapy. See Remington'sPharmaceutical Sciences, Ed. XIII, pages 547 to 548, 1965, published byMack Publishing Co., Easton, Pa., and An Introduction to PharmaceuticalFormulation, by Fishburn, page 116, 1965, published by Pergamon PressLtd., New York, N.Y.

Recent advances for administering a drug to the eye are disclosed inU.S. Pat. Nos. 3,416,630 and 3,618,604 owned by Applicant. These patentsdescribe ocular inserts that act as a depot or drug reservoir for slowlyreleasing drug to the eye for prolonged periods of time. The inserts arefabricated or flexible polymeric materials that are biologically inert,non-allergenic, and insoluble in tear fluid. To initiate the therapeuticprogram, these ocular inserts are placed in the cul-de-sac between thesclera of the eyeball and the eyelid for administering drug to the eye.Since the ocular inserts are formed of polymeric materials that areinsoluble in tear fluid, they retain their shape and integrity duringthe course of the needed therapy to serve as a drug reservoir forcontinuously administering drug to the eye and the surrounding tissuesat a rate that is not affected by dissolution or erosion of thepolymeric material. The ocular insert, on termination of the desiredtherapeutic program, is removed from the cul-de-sac. Thus, the insertsof the above-mentioned patents provide a complete ophthalmic dosageregime for a prolonged period of time, generally on the order of 24hours or longer.

The device of U.S. Pat. No. 3,416,530 is manufactured with a pluralityof capillary openings that communicate between the exterior of thedevice and an interior chamber generally defined from a polymericmembrane. While these capillary openings and this construction areeffective for releasing drug to the eye, they add considerablecomplexity to the manufacture of the device because it is difficult tocontrol the size of these openings in large scale manufacturing usingvarious polymers as required for various drugs.

The device of U.S. Pat. No. 3,618,604 does not involve such capillaryopenings, but instead provides for the release of drug by diffusionthrough a polymeric membrane at a drug release rate that can becontrolled with precision and reproducibility. The device, in apreferred embodiment, as disclosed in that patent, comprises a sealedcontainer having the drug in an interior chamber. While remarkablyeffective for administering drug, certain problems have been encounteredin manufacturing the devices. For example, one problem is the difficulttask of sealing the margins of the membrane to form the container.Another problem met in making such device when drug in solid form iscontained therein, is the stresses and strains introduced into themembrane walls for deformation during manufacture in forming thereservoir, causing the device, in many instances, to rupture and leak.In addition, this causes entrappment of air and the alteration of therelease chaaracteristics of the membrane. A further problem with suchdevices when used for containing drug in liquid form, is that duringmanufacture, the liquid spreads and wets the sealable surfaces. Thesewet surfaces cannot be sealed to make a device essentially free ofleaks.

SUMMARY OF THE INVENTION

Accordingly, it is an immediate object of this invention to provide anocular device for the administration of a locally or systemically actingdrug to produce a physiologic or pharmacologic effect which deviceovercomes the problems of the prior art.

A further object of this invention is to provide a dosage regimen foradministering a drug to the eye for a particular time period, the use ofwhich requires intervention only for initiation and termination of theregimen.

Still another object of this invention is to provide an ocular insertwhich is comfortable to wear for long periods and does not causediscomfort during sleeping and normal daily wear while simultaneouslyadministering drug to the eye.

Yet another important object of the invention is to provide an oculardevice of construction and design so as to eliminate unwanted drug leaksand membrane failures during use.

Still a further object of this invention is to provide a process formaking such new ocular drug dispensing devices.

Another object of the invention is to provide a ocular device for thecontrolled release of drug having enhanced mechanical and physicalproperties.

In accomplishing the objects, features and advantages, the invention issummarized in one aspect as an ocular delivery device for the continuousadministration of drug over a prolonged period of time comprising asealed container shaped for insertion into the eye, the container havinga pair of separate and discrete first and third membrane walls spacedfrom each other, each formed of a material insoluble in tear fluid, withat least one of the membrane walls being permeable to the passage ofdrug by diffusion at a controlled rate, and a second ring-shaped wallinterposed between and sealing engaging the first and third membranewalls along their outer faced peripheries to define an integral unit andform a closed reservoir defined by the inner surfaces of the first,second and third walls, said reservoir containing drug which is releasedfrom the reservoir at a controlled rate by passage through the ratecontrolling membrane wall. The device, in a preferred embodiment, isshaped and adapted for insertion and comfortable placement in thecul-de-sac of the conjunctiva between the sclera of the eyeball and theeyelids.

Other objects, features, and advantages of the invention will beapparent to those skilled in the art from the following detaileddescription of the invention, taken in conjunction with the drawings,and the accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not drawn to scale, but are set forth toillustrate various embodiments of the invention, the figures are asfollows:

FIG. 1 is a top plan view of an ocular device illustrating the topmembrane wall and the annular ring.

FIG. 2 is an enlarged cross-sectional view of a device depicting the twomembrane walls with their interior peripheral surfaces in contact withthe surface of the spacer middle wall positioned between the membranewalls.

FIG. 3 is an exploded view illustrating the elements prior to theirunion wherein they act in concert to form an integral device.

FIG. 4 is a partly diagrammatic, front elevational view of a human eyeillustrating an ocular device in operative position after its insertioninto the eye.

FIG. 5 is a view partly in vertical section and partly diagrammatic ofan eyeball and the upper and lower eyelids associated therewith showingthe ocular insert in operative position.

In the drawings and specification, like parts in related figures areidentified by like numbers. The terms appearing earlier in thespecification and in the description of the drawings, as well asembodiments thereof, are further described elsewhere in the disclosure.

DETAILED DESCRIPTION OF THE DRAWINGS

Turning now to the drawings in detail which are examples of oculardevices of the invention, and which examples are not to be construed aslimiting, one embodiment of a device is indicated in FIG. 1 by numeral10. Device 10 is comprised of membrane wall 11 formed of a release ratecontrolling material permeable to the passage of a drug 14 by diffusion.Wall 11 carries on its inner surface an inner positioned wall 12,schematically illustrated by dashed lines, which wall 12 extends aroundthe perimeter of wall 11 to engage it in sealed relation with anotherwall, not shown in FIG. 1, distant from wall 11 to form device 10.

Referring to FIG. 2, ocular drug delivery device 10 is seen incross-section along line 2--2 of FIG. 1. As seen in FIG. 2, device 10 iscomprised of a first separate and discrete membrane wall 11 and a thirdseparate and discrete membrane wall 14 distant from the first wall 11.Wall 11 and wall 14 bear on their inner surfaces a second wall 12 thatextends around the outer perimeter of wall 11 and wall 14 to form aclosed reservoir 15. Reservoir 15 contains a drug 13, or a mixture ofdrugs. Wall 11 and wall 14 can be the same or they can be different andat least one of the walls, 11 or 14, or both of the walls, is comprisedof a flexible, substantially homogenous, substantially imperforate drugrelease rate controlling material permeable to the passage of drug 13 asby diffusion. Alternatively, at least one of the walls, 11 or 14, iscomprised of a flexible microporous material, the micropores of whichcontain a drug release rate controlling medium permeable to the passsageof drug 13, as by diffusion. When one of walls 11 and 14 is permeable tothe passage of drug 13, the distant wall can optionally be formed of amaterial essentially impermeable to the passage of drug or of a materialpermeable to drug of either the homogenous or microporous typesdescribed above. Wall 12 of device 10 is formed of a flexible,non-allergenic, biologically inert, material insoluble in tear fluidwhich is suitable for joining wall 11 and wall 14 together to form anessentially closed reservoir 15 as defined by the inner surfaces of thewalls 11, 12 and 14. Drug 13 is preferably in a solid, semi-solid, orgel form, either alone or mixed with a carrier. In the case of drugswhich are liquids, such drug is preferably compounded with a gellationagaent to form a solid or gel suitable for incorporation in thereservoir 15 as hereinafter described.

The parts of device 10 act in concert as an ocular drug dispensingdevice to effectively dispense a drug to the eye and to its surroundingtissues at a controlled and continuous rate for a prolonged period oftime, When wall 11 or wall 14 is comprised of a material that issubstantially homogeneous and imperforate, molecules or drug dissolve inand migrate through the material itself by diffusion. When wall 11 orwall 14 is made from a microporous material, molecules of drug migrateby diffusion through a liquid phase present in the pores of themicroporous material. Wall 11 or wall 14 may also be made from amaterial which is both microporous and homogenous. Drug can be releasedto the eye by diffusion through a diffusive medium within the pores ofthe material and by diffusion through the polymer as such.

Wall 12, positioned between wall 11 and wall 14, functions as a bondingor joining wall used essentially for joining wall 11 and wall 14 in aspaced relationship. Wall 12 is formed of a material that readily lendsitself for sealingly engaging wall 11 and 14 to form a flexible, sealeddevice. Wall 12 may be optionally comprised of a material permeable orimpermeable to drug since its exposed surface area in contact with theeye and its surrounding tissues is small compared with the total exposedsurface area of walls 11 and 14. The shape of wall 12 as seen from FIG.3 is ring-like and this term is meant to also include elliptical, ovalor any other geometric shape which extends around the perimeter of themembrane walls.

Referring to FIG. 4, device 10 is shown positioned in immediate contactwith an eye 16 for administering a drug thereto. Eye 16 is comprised ofan upper eyelid 17 with eyelashes 19 at the edge of eyelid 17 and alower eyelid 18 with eyelashes 20 at the edge of eyelid 18. Eye 16anatomically is comprised of an eyeball 22 covered for the greater partof its posterior area by a sclera 24 and at its central area by acornea. Eyelids 17 and 18 are lined with an epithelial membrane orpalpebral conjunctiva, not shown, and sclera 24 is lined with a bulbarconjunctiva which covers the exposed surface of eyeball 2. Cornea 21 iscovered with a transparent epithelial membrane, not shown. The portionof the palpebral conjunctiva which lines upper eyelid 17 and theunderlying portion of the bulbar conjunctiva defines an uppercul-de-sac, not seen in FIG. 4, while that portion of the palpebralconjunctiva which lines lower eyelid 18 and the underlying portion ofthe bulbar conjunctiva define a lower cul-de-sac, not seen in FIG. 4.Device 10 may be shaped and sized for insertion in the cul-de-sac of theconjunctiva between sclera 24 of eyeball 22 and upper eyelid 17, or asseen in broken continuous line, may be shaped and sized for positioningin the cul-de-sac of the conjunctiva between the sclera 24 of eyeball 22and lower eyelid 18, generally to be held in position by the naturalpressure of the respective eyelid.

In FIG. 5, eye 16 is shown in horizontal section with device 10 inposition to dispense drug. Eye 16 is comprised of upper eyelid 17 andlower eyelid 18, with their respective eyelashes 19 and 20, eyeball 22,cornea 21 and sclera 24. An upper cul-de-sac 26 and a lower cul-de-sac23 are defined by a conjunctiva 25. Device 10 is positioned in lowercul-de-sac 23 to continuously dispense a predetermined amount of drug ora combination of drugs from the device to the eye and its surroundingtissues over a prolonged period of time. In operation, after drug leavesthe device, it is transported to the eye and its surrounding tissues, byphysiological processes such as the flow of tear liquid and blinkingaction of the eyelids.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the practice of the invention, it has been found thedevice of this invention provides many important advantages overpreviously known ocular drug delivery devices. One advantage of thedevice is the ease of construction by standard manufacturing techniquesinto devices of various sizes, shapes and forms. For example, the devicecan be of any convenient geometric shape for comfortable retention inthe eye. Typical shapes include ellipsoid, bean-shaped, banana-shaped,circular-shaped, retangular-shaped, trapezoidal and doughnut-shaped. Incross-section, it can be doubly convex, concavo-convex, and rectangularas the device during use, will tend to conform to the configuration ofthe eye. The dimensions of the device can vary with the size of thedevice, the amount of drug in the device's reservoir, the membrane whichgoverns the rate drug is to be administered, and by the size of the eye.Satisfactory devices generally have a length of 4 to 20 millimeters, awidth of 1 to 15 millimeters, and a thickness of 0.1 to 4 millimeters, areservoir with a diameter of 1.2 to 14.8 millimeters, and contain from 1microgram to 100 milligrams of drug or more.

Materials suitable for fabricating the wall(s) of the imperforate,substantially homogenous type described above, include naturallyoccurring or synthetic materials that are biologically compatible withbody fluids and eye tissues, and essentially insoluble in body fluidswith which the material will come in contact. The use of rapidlydissolving materials or materials highly soluble in eye fluids is to beavoided since dissolution of the wall affect the constancy of the drugrelease, as well as the capability of the system to remain in place fora prolonged period of time. Exemplary naturally occurring or syntheticmaterials suitable for fabricating such walls arepoly(methylmethacrylate), poly(butylmethacrylate), plasticizedpoly(vinylchloride), plasticized nylon, plasticized soft nylon,plasticized poly(ethylene terephthalate), natural rubber,poly(isoprene), poly(isobutylene), poly(butadiene), poly(ethylene),poly(tetrafluoroethylene), poly(vinylidene chloride),poly(acrylonitrile, cross-linked poly(vinylpyrrolidone),poly(trifluorochloroethylene), chlorinated poly(ethylene),poly(4,4'-isopropylidene diphenylene carbonate), ethylene-vinyl acetatecopolymer, plasticized ethylene-vinyl acetate copolymer, vinylidenechloride-acrylonitrile copolymer, vinyl chloride-diethyl fumeratecopolymer, silicone rubbers, especially the medical gradepoly(dimethylsiloxanes), ethylene-propylene rubber, silicone-carbonatecopolymer, vinylidene chloride-vinyl chloride copolymer, vinylchloride-acrylonitrile copolymer and vinylidene chloride-acrylonitrilecopolymer.

As stated above, such homogenous imperforate materials dispense drug bya process of diffusion. In that process, the drug dissolves andequilibrates in the material at the inner surface of the wall, and thendiffuses in the direction of lower chemical potential, i.e., toward theexterior surface of the wall. At the exterior surface of the wall,equilibrium is again establihsed. When the conditions on both sides ofthe wall are maintained constant, a steady state flux of the drug willbe established in accordance with Fick's Law of Diffusion. The rate ofpassage of the drug through the material by diffusion is generallydependent on the solubility of the drug therein, as well as on thethickness of the wall. This means that selection of appropriatematerials for fabricating the wall will be dependent on the particulardrug to be used. By varying the composition and thickness of the wall,varying dosage rates per area of the ocular device can be obtained.

Materials of the microporous type suitable for fabricating the wall(s)have pores which range in size from several angstroms, usually at leastabout 10A, to several hundred microns, but usually not more than about100 microns. The porosity of these materials may range between about 5%and about 95%. Exemplary microporous materials are regenerated,insoluble, nonerodible cellulose, acylated cellulose, esterifiedcelluloses, cellulose acetate propionate, cellulose acetate butyrate,cellulose acetate phthalate, cellulose acetate diethyl-aminoacetate,poly(urethanes), poly(carbonates), microporous polymers formed bycoprecipitation of a polycation and a polyanion as described in U.S.Pat. Nos. 3,276,589, 3,541,005; 3,541,006 and 3,546,142, modifiedinsoluble collagen, cross-linked poly(vinyl alcohol) with a pore size of7 to 50 A, epoxy resins and poly(olefins) or poly(vinylchlorides) with apore size of about 50 A or less to 150 microns or larger as convenientlymade by leaching out incorporated salts, soap micelles, starch or likematerials to give a microporous membrane. Also, the materials that canbe used include those materials having homogenous properties andmicroporous properties, such as cross-linked gelatinous membranes. Asindicated above, such microporous materials dispense drug by a processin which the drug diffuses through a diffusive medium in the pores ofthe material. In this process, the drug molecules dissolve in the mediumat the interior surface of the wall and flow through the medium in adirection of lower chemical potential, that is, to the exterior surfaceof the wall. A drug will have a definite and characteristic rate ofdiffusion through the diffusive medium which is generally dependent onthe solubility of the drug in the diffusive medium, the thickness andporosity of the release rate controlling material and the tortuosityfactor.

The diffusive media suitable for use with the microporous materials arethose materials which are non-toxic in the eye and surrounding tissuesand in which the drug has a limited solubility so that the drug isreleased by diffusion rather than by simple dissolution which isdifficult to control. By "limited solubility" is meant that drug issoluble in given selected amounts in the diffusive medium and includessolubilities such as soluble, sparingly soluble, slightly soluble, veryslightly soluble, and almost practically insoluble. Generally, the termlimited solubility comprises a range of solubility of drug in medium offrom 10 parts per million to 10,000 parts per million on a weight basis.

The medium can be a liquid, a gel, a colloidal solution, a sol, and thesolution can be polar, semi-polar, or non-polar. Representative mediumsare saline, glycerin, ethylene glycol, propylene glycol, water,emulsifying and suspending agents such as methyl cellulose mixed withwater, mixtures of propylene glycol monostearate and oils, gumtragacanth, sodium alginate, poly(vinyl pyrrolidone), poly(oxyethylenestearate), fatty acids such as linoleic, and silicone oil. Otherrepresentative mediums are set forth in Remington's PharmaceuticalSciences, pages 246 to 269 and 1338 to 1380, 1970, published by MackPublishing Company, Easton, Pa.

The diffusive medium can be added to the microporous material by methodswell known to the art, for example, by immersion of the material in abath containing the diffusive medium to let the medium partially fill orfully saturate the micropores of the material. Another method forcharging the micropores with a diffusive medium is to add the diffusivemedium or a mixture of diffusive media with the drug formulation so thatthe medium can flow from within the reservoir into the pores and remaintherein to permit diffusive flow of drug. In a preferred aspect, thediffusive medium is an isotonic solution such as lachrymal fluid whichcan be incorporated into the pores of the microporous material by way ofthe previously described methods or advantageously incorporated bycontact with the eye at the time the ocular device is inserted in theeye, in which case, these fluids are available for subsequent transferinto the micropores of the material for functioning as a diffusivemedium for drug.

Materials suitable for forming the second wall that is interposedbetween the first and third walls and sealingly joins the same at theirperimeters are naturally occurring and synthetic materials that canserve as a cold setting adhesive or as a hot setting adhesive withtackiness while simultaneously retaining their polymeric integrity toserve as the middle wall and assist the two spaced walls defining thereservoir. The phrase cold setting adhesive as used herein indicatespolymeric materials that are tacky and will bond other polymericmaterials at set temperatures from 5°C to 50°C, and the phrase hotsetting adhesive is used to indicate a polymeric material that is tackyand will bond other polymers at set temperatures from 50°C to 250°C. Theterm tacky generally indicates stickiness of a polymeric material tointimately bond two walls together. The operable temperatures for suchbonding polymers can easily be ascertained by standard techniques as setforth in Modern Plastic Encyclopedia, Vol. 46, No. 10A, 1969, and inASTM Standards, Structural Sandwich Constructions, Part 16, T. PeelTest: ASTEMD 1876-61 T. Peel Resistance, 1965, published by the AmericanSociety for Testing and Materials, and like references. Exemplarymaterials are poly(vinylacetate), cross-linked poly(vinyl alcohol),cross-linked poly(vinylbutyrate), ethylene-ethyl acrylate copolymer,poly(ethylhexylacrylate), poly(vinylchloride), poly(vinyl acetals),plasticized ethylene-vinyl acetate copolymer, poly(vinyl alcohol),poly(vinylacetate) ethylene-vinylchloride copolymer, poly(vinylesters),poly(vinylbutyrate), poly(vinylformal) and polyamides.

The use of an intermediate second wall in the devices provides severaladvantages. It enables easy manufacture of a sealed container frommaterials of different drug diffusion properties. Also colors, that isdyes, may be incorporated into the second wall to serve to identifydifferent drugs, different sized devices and dates of manufacture.Additionally, the dye is not mixed with the drug so potential dye-drugcomplexes are avoided. Another important advantage of the middle wall isits ability to function as an adhesive to seal together at lowtemperatures like walls or unlike walls into a composite article ofmanufacture. Thus, walls formed of materials like poly(vinylchloride)that would require a high sealing temperature, e.g., 200°C or higher,can be hermetically sealed by using a middle wall of, for example,ethylene-vinyl acetate copolymer that serves as a hot melt adhesive tojoin the first and third walls at a much lower temperature.Additionally, the middle wall by functioning as a hot helt adhesive, canbe used to seal generally unsealable walls, for example, walls formed ofunplasticized cellulose acetate. Sealing at low temperature alsoprotects the drug from exposure to high temperatures that could alter oradversely affect the drug.

Still another important advantage obtained by the use of the middlering-shaped wall is the desirable physical and mechanical propertiesimparted thereby to the device by substantially eliminating entrappedair and unwanted stresses and strains introduced into the membrane wallsduring manufacture that lead to ruptures and leaks during use. Theelimination of such stresses and strains enhances the flexibility of thedevice, thereby increasing its ability to be retained in the eye. Inaddition, the achievement of precision release of drug from the deviceis made possible by the inclusion of the middle annular wall. This is sosince the elimination of unwanted stresses and strains enables themembrane walls to be of uniform characteristics necessary to obtain thedesired degree of control over the kinetics of drug release.

As used herein, the term drug broadly means compositions administrableto the eye and its surrounding tissues to produce a local or a systemicphysiologic or pharmacologic beneficial effect. Examples of drugsinclude antibiotics such as tetracycline, chlortetracycline, bacitracin,neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol,gentamycin, and erythromycin; antibacterials such as sulfonamides,sulfacetamide, sulfamethizole and sulfisoxazole; antivirals, includingidoxuridine; and other antibacterial agents such as nitrofurazone andsodium propionate; antiallergenics such as antazoline, methapyriline,chlorpheniramine, pyrilamine and prophenpyridamine; anti-infammatoriessuch as hydrocortisone, hydrocortisone acetate, dexamethasone,dexamethasone 21-phosphate, fluocinolone, medrysone, prednisolone,methylprednisolone, prednisolone 21-phosphate, prednisolone acetate,fluoromethalone, betamethasone and triaminolone; decongestants such asphenylephrine, naphazoline, and tetrahydrazoline; miotics andanticholinesterases such is pilocarpine, eserine salicylate, carbachol,di-isopropyl fluorophosphate, phospholine iodide, and demecariumbromide; mydriatics such as atropine sulfate, cyclopentolate,homatropine, scopolamine, tropicamide, eucatropine, andhydroxyamphetamine; and sympathomimetics such as epinephrine. Generally,an ocular drug delivery device will contain from 1 microgram to 100milligrams of drug or more, for releasing the drug to the eye at artknown dosage rates. For example, an ocular drug delivery device canadminister 5 to 200 micrograms per hour of pilocarpine and itsderivatives for 24 hours to an adult human, or for simultaneousadministration of 5 to 120 micrograms of pilocarpine hydrochloride and10 micrograms to 0.5 milligrams of hydrocortisone acetate for a dailydose, and the like as described in Physicians' Desk Reference, DrugClassification Index, Ophthamologicals, page 217, and entries citedtherein, Twenty-Forth edition, 1969, Medical Economics, Inc.

Drugs can be in various forms, such as uncharged molecules, componentsof molecular complexes, or non-irritating, pharmacologically acceptablesalts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate,borate, acetate, maleate, tartrate and salicylate. For acidic drugs,salts of metals, amines, or organic cations, for example, quaternaryammonium can be employed. Furthermore, simple derivatives of the drugssuch as ethers, esters, amides, and the like, which have desirableretention, release, or solubility characteristics, and which are easilyhydrolized by body pH, enzymes, or other metabolic processes, can beemployed.

The drug is desirably present in the interior reservoir defined by thewalls of the device in a manner, mode and quantity in which it will bein intimate contact, at a constant thermodynamic activity, with thedrug-permeable wall(s) of the device throughout the administrationperiod. For this purpose, and for fabricating convenience, it willpreferably be present together with a drug-permeable solid or semi-solid(e.g., a gel or colloid) carrier which provides a formulation which maybe cast or otherwise formed into a body which may be readily handled andassembled in combination with the walls. In this regard, it is possibleto use liquid drugs or liquid drug formulations in the devices of thisinvention. However, the use of such liquids presents greater handlingand assembling problems than the use of solid or gelled materials. Ithas been found that when the drug is in a liquid form, it is preferableto compound or mix the drug with a gel-forming agent. The agents areused for gellation of liquid drugs for improving the handling, fillingand sealing of the device. By gelling a liquid drug to a film,suspension or solid, it is easier to handle and place drug into areservoir. The solid or film is formed by mixing a gel-forming agentwith the liquid drug, followed by shaping to fit the reservoir; or, thereservoir can be filled with the mixture immediately before gellationwith the latter occurring in situ. The gel-forming agents can be ofnaturally occurring or of sythetic origin, and either hydrophobic orhydrophilic. The agent can be a polysaccharide such as a linear neutralor a branched neutral polysaccharide, or a polysaccharide with basic,carboxyl or other acid groups such as a natural gum, a seaweed extract,a plant exudate, a seed gum, a plant extract, or an animal extract, or abiosynthetic gum. Typical gel-forming agents include agar, agarose,algin, sodium alginate, potassium alginate, carrageenan,kappa-carrageenan, lambda-carrageenan, fucoidan, furcellaran, laminaran,hypnea, eucheuma, gum arabic, gum ghatti, gum karaya, gum tragacanth,guar gum, locust bean gum, guince psylluim, flax seed, okra gum,arabinoglactin, pectin, xanthan, scleroglucan, dextran, anylose,amylopectin, dextrins, and synthetic gel-formers such asmethylcellulose, hydroxyalkyl derivatives of cellulose wherein the alkylis 1 to 7 carbons, ethylhydroxyethylcellulose, and sodiumcarboxymethylcellulose.

To readily maintain such thermodynamic activity, the drug should havelimited solubility in the carrier and be present in sufficient excess toinitially saturate the carrier and maintain such saturation during thedrug administration period. By limited solubility is meant that drug issoluble in given amounts in the carrier, that is, it comprises varyingconcentrations of drug dissolved in the carrier. In most instances, thedrug will be soluble in the carrier in amounts ranging between 10 and10,000 p.p.m. As indicated above, there is also an excess amount ofundissolved drug present in the carrier. The initial fractional amountof drug dissolved in the carrier will usually be in the range of 0.1% to35% by weight of the total amount of drug. In any event, there should besufficient undissolved drug incorporated to serve as a reserve source ofdrug for replacing released drug by dissolving in the carrier to keepthe concentration during the history of the ocular device, or until theocular device is no longer used. Examples of solid and semi-solidcarriers are gelatin, starches, carbohydrates, solid extracts, curedpolymers, silicone carbonate copolymers, plasticized polymers,hydrophilic polymers such as hydrophilic hydrogels of esters of acrylicacids, modified collagen, surface treated silicone rubber, alginic acidand derivatives thereof, pectin and plasticized poly(vinylchloride). Thecarrier can also contrain adjuvants such as preserving, stabilizing, orwetting agents.

The materials forming the drug-permeable wall and the carrier arepreferably chemically and structurally different within a single device.The permeability of the wall to drug should be lower than is thepermeability of the carrier to drug to ensure that release kinetics ofthe device are controlled by the wall.

The carrier-drug mixture may be prepared by standard mixing techniquessuch as ballmilling, calendering, shaking and rollmilling.

The process for making the above-described ocular drug dispensingdevices comprises:

forming a first wall from a material insoluble in tear fluid andoptionally permeable to drug at a predetermined rate and in a shape andsize adapted for insertion in the eye;

forming a second wall from a material insoluble in tear fluid in a ringshape having an outer perimeter of generally the same shape as theperimeter of the first wall;

placing the second wall on the first wall with the outer perimeter ofthe second wall in general registry with the perimeter of the firstwall;

charging drug onto the surface of the first wall in the area thereofbounded by the inner perimeter of the second wall;

forming a third wall from a material insoluble in eye fluid andoptionally permeable to drug at a predetermined rate, with the provisothat at least one of the first and third walls is permeable to drug at apredetermined rate, in the same general shape as the first wall;

placing the third wall over the drug with its perimeter in generalregistry with the outer perimeter of the second wall and its peripherycontacting said second wall; and

sealing the first and third walls to the second wall.

When the drug is of a liquid nature, it is preferred to mix or react thedrug with a gelling agent as heretofore described, to form a solidcomposition prior to charging the formulation onto the surface of thefirst wall.

Thus, more particularly and in accordance with the above, the device maybe assembled by standard procedures such as by molding or casting thefirst wall, pressing the second annular wall thereto, extruding druginto the reservoir, then sealing the third wall in place as shown in thedrawing. The walls can be sealed together by various methods such ashigh frequency electronic sealing that provides clean edges and firmlysealed ocular devices. By using, for example, high frequency sealing,the wall-forming materials flow-melt at the point of contact to suitablyjoin the walls into a composite article of manufacture. The ability todesign and shape the walls into an ocular device of high reproducibleshapes, readily results in fabrication of ocular drug delivery deviceswith reproducible dispensing properties and thus overcomes a significantdisadvantage of previously described devices. Other standardmanufacturing procedures are described in Modern Plastics Encyclopedia,Vol. 46, pages 62 to 79, 1969, and may be readily adapted by thoseskilled in the art to fabricate the ocular device of the invention.

The rate of release of a drug through various materials in the pores ofthe microporous wall can be easily determined by those skilled in theart by standard procedures, as described in Encycl. Polymer Science andTechnology, Vols. 5 and 9, pages 65 to 82 and 794 to 807, 1968, and thereference cited therein, in Membrane Science and Technology, by Flinn,James E., pages 16 to 32 and 120 to 138, 1970, published by PlenumPress, Inc., and in Chemical Engineers Handbook, pages 17-42 to 17-45,1963, published by McGraw Hill, Inc. One applicable method employsFick's Law of Diffusion, wherein the flux of drug through aconvection-free medium, for example, a liquid present in a porousmembrane, is given by the equation: ##EQU1## wherein J is the flux ingm/cm² sec., ε is the porosity in cm³ /cm³, τ is the tortuosity factor,D is the diffusion coefficient cm² /sec., and dc/dχ is the drugconcentration gradient across the barrier.

Thus, when the diffusion coefficient is assumed to be independent ofconcentration, and the concentration at the outside surface isnegligibly small, the equation can be expressed as follows: ##EQU2##wherein C_(s) is the saturation solubility of the drug in the diffusivemedium, and l is the barrier thickness.

The diffusion coefficient D will be in the order of 2 × 20.sup.⁻⁶ cm²sec.sup.⁻¹ when the drug has a small molecular diameter, for example,about 10 A and the pore diameter of the microporous wall is large incomparison with the molecular drug diameter, for example, at leastgreater by a factor of 10. However, when the pore diameter of the ratecontrolling membrane is reduced relative to that of the molecular drugdiameter, for example from 10 to about 3 times the molecular diameter,the diffusion coefficient D will decrease to values as low as 2 ×10.sup.⁻⁸ cm² sec.sup.⁻¹. When the ratio of membrane pore diameter tomolecular drug diameter significantly is below about 3, the membranesare considered to be homogenous solution diffusion materials. By varyingpore diameter or porosity of the microporous materials, substantialchanges in release rate can be brought about while still using the samematerials.

The rate of release of a drug through various homogenous walls can bedetermined by standard procedures. In this manner, particularimperforate materials used as the device's wall for the release ratecontrolling barriers can be selected. Various techniques, such as thetransmission method and the sorption-desorption method, can be used asmeasurers of permeability. One technique that has been found to be wellsuited is to cast or hot press a film of the material to a thickness inthe range of 2 to 60 mils. The film is used as a barrier between arapidly stirred (e.g., 150 r.p.m.) saturated solution of the drug and arapidly stirred solvent bath, both maintained at constant temperature(typically 37°C). Samples are periodically withdrawn from the solventbath and analyzed for drug concentration. By plotting the drug'sconcentration in the solvent bath versus time, the permeability constantP of the material is determined by the Fick's First law of Diffusion.##EQU3## wherein Q₁ = cumulative amount of drug in solvent in microgramsat t₁ Q₂ = cumulative amount of drug in solvent in micrograms at t₂, t₂= elapsed time to first sample, i.e., Q₁, t₂ = elapsed time to secondsample, i.e., Q₂, A = area of membrane in cm², C = initial concentrationof drug, h = thickness of membrane in cm.

By determining the slope of the plot, i.e. (Q₁ - Q₂)/(t₁ - t₂), andsolving the equation using the known or measured values of A, C, and h,the permeability P constant in cm² /time of the material for a givendrug is readily determined. The rate of drug release through differentrelease rate controlling materials can be easily determined by thoseskilled in the art by standard procedures, as described in Encycl.Polymer Science and Technology, Vols. 5 and 9, pages 65 to 82 and 794 to807, 1968, and the references cited therein, in J. Pharm. Sci., Vol. 52,pages 1145 to 1149, 1963, ibid., Vol. 53, pages 798 to 802, 1964, ibid.,Vol. 54, pages 1459 to 1464, 1965, ibid., Vol. 55, pages 840 to 843 and1224 to 1239, 1966, Encycl. Polymer Science and Technology, Vols. 5 and9, pages 65 to 82 and 794 to 807, 1968, and the reference cited therein.

The solubility of a drug in a diffusive medium can be determined by artknown techniques. One method consists in preparing a solution of thedrug and ascertaining by analysis the amount of drug present in adefinite quantity of the medium. A simple apparatus for this purposeconsists of a test tube fastened upright in a water bath maintained atconstant temperature. The medium and drug are placed in the tube andstirred by a motor driven rotating spiral. After a given period ofstirring, a known weight of the medium is analyzed and the stirringcontinued for an additional period of time. If the analysis shows noincrease of dissolved substance after the second period of stirring, theresults are taken as the degree of solubility of the drug in the medium.Numerous other methods are available for the determination of the degreeof solubility of a drug in a liquid medium. Typical methods used for themeasurement of solubility are chemical analysis, measurement of density,refractive index and electrical conductivity. Details of various methodsfor determining solubilities are described in United States PublicHealth Service Bulletin No. 67 of Hygienic Laboratory, Encycl. ofScience and Technology, Vol. 12, pages 542 to 556, 1971, McGraw-Hill,Inc., Encylopaidic Dictionary of Physics, Vol. 6, pages 545 to 557,1962, Pergamon Press, Inc., and the like.

The solubility of the drug in the carrier is determined by preparing asaturated solution of drug and ascertaining, by analysis, the amountpresent in a measured area of the carrier. For example, the solubilityof the drug in the carrier is determined by first equilibrating thecarrier with a saturated solution of the drug at a known temperature,for example 37°C, or with a pure liquid drug, if the drug is a liquid at37°C. Next, drug is desorbed from the saturated carrier with a suitablesolvent for the drug. The resultant solution is analyzed by standardtechniques such as ultraviolet, visible spectrophotometry, refractiveindex, polarography, and electrical conductivity, and from datacalculating the concentration or solubility of the drug in the solidcarrier.

The diffusion coefficient of a drug is determined by measuring the ratea drug transfers from one chamber through a sintered glass filter ofknown pore size and thickness into another chamber and calculating fromthe obtained data the drug transfer rate. The method when used for adiffusive medium, is carried out by adding to a first conical flaskequipped with a ground glass stopper and a stirring bar, a measuredamount of medium and simultaneously, the drug in the same medium isadded to a second concial flask while keeping the level of the medium inthe two flasks the same. Next, the flasks are stirred, the samples drawnat various time intervals for analysis. The measured rate of drugtransport through the sintered glass filter, and the concentrationdifference of the drug in the two flasks is then calculated. Theseprocedures are known to the art in Proc. Roy. Sci. London, Ser. A, Vol.148, pages 1935, J. Pharm. Sci., Vol. 55, pages 1224 to 1229, 1966 andreferences cited therein. The diffusion coefficient of a drug in thesolid carrier also can be experimentally determined by using the aboveapparatus or similar apparatus and procedures as described in Diffusionin Solids, Liquids and Gases, by Jost, W., Chapter XI, pages 436 to 488,1960, Revised Edition, Academic Press, Inc., New York.

The solubility of the drug in the release rate controlling materialcomprising the homogenous wall is determined by preparing a saturatedsolution of a given drug and ascertaining the amount present in an areaof the material. For example, the solubility of the drug in thehomogenous wall is determined by first equilibrating the wall materialwith a measured saturated solution of the drug at a known temperatureand pressure, for example 37°C and 1 atmosphere. Next, drug is desorbedfrom the saturated homogenous material with a suitable solvent. Theresultant solution for the drug then is analyzed by standard techniquessuch as ultraviolet, visible spectrophotometry, refractive index,polarography, and electrical conductivity. From the data obtained, theconcentration or solubility of the agent in the material is calculated.

The following examples are merely illustrative of the present inventionand they should not be considered as limiting its scope in any way.

EXAMPLE 1

An ocular drug dispensing device of elliptical shape and comprised oftwo outer release rate controlling walls each fused to an inner middlewall having a center area defining a space and which middle wall extendsaround the interbonds the internal perimeter of the two outer walls toform an ocular drug dispensing device having a reservoir for containinga drug defined by the internal surfaces of all the walls is manufacturedas follows: first, a uniform wall material is formed by dissolvingcommercially available ethylene-vinyl acetate copolymer in methylenechloride in a concentration ratio or 20% copolymer to 80% solvent andfilm casting the solution onto a glass substrate. The solvent is allowedto evaporate at room temperature and the film warm air dried to yield afilm about 1.7 ± 0.2 mols thick. Two walls, about 16 mm × 6.75 mm, arepressed from the film for use as the drug release walls of the oculardevice. Next, a middle wall is prepared by mixing ethylene-vinyl acetatecopolymer, methylene chloride and Food Drug and Cosmetic blue lake dyein a percent ratio of 20 to 80 to 0.1 and the ingredients thoroughlymixed in a commercial, laboratory v-blender. The mixture is cast onto aglass surface, and the solvent evaporated at room temperature. Then, thefilm is warm air dried to yield a film 4.2 ± 0.3 mils thick. Next, thisfilm is press-cut into an ellipse having the same dimensions of the justpress-cut walls. The middle wall is press-cut with the center areapunched out to yield a continuous ellipse defining an opening. Then,onto one of the drug release walls is placed a middle wall and these twowalls placed into a conventional standard vacuum laminator. Next, avacuum is pulled to 74 cm. of mercury and held for three minutes. At theend of three minutes, a high flux radiant heater is positioned over thewalls and heated for about 15 seconds or until the temperature reachesabout 70°C. At the end of the heating, a pressure head is applied to thewalls and a pressure of 6.8 Kg. applied for 45 seconds to firmly sealthe two walls, and the vacuum released.

Next, to 500 grams of sterile, distilled water is added 300 grams ofpilocarpine base and 25 grams of alginic acid and the ingredients wellmixed in a standard v-blender, and following the mixing, cast on a cleanglass plate. The water is evaporated at room temperature to yield analginic acid-pilocarpin drug core, of approximately 92.3% pilocarpinebase and 7.7% alginic acid. A 7.0 ± 1.0 mg aliquot of the drug core isthen deposited into the two wall laminate, and the third wall placed incontact with the middle wall. The three walls are then vacuum heatlaminated as just described to produce a composite article ofmanufacture. The resulting device, when placed into an adult human eye,will administer 50 micrograms of pilocarpine per hour for 24 hours.

EXAMPLE 2

An ocular drug delivery device for the continuous and controlled rate ofdrug administration over a prolonged time is manufactured from drugrelease rate controlling material insoluble in eye fluid according tothe procedure as described in Example 1 with the drug reservoir in thisembodiment comprised of pilocarpine and alginic acid wherein the ratioof pilocarpine to alginic acid is from 12 to 1 and from 3 to 1 for thecontrolled release of the drug to the eye.

EXAMPLE 3

An ocular device for the prolonged administration of drug is madeaccording to the procedure of Example 1 with the pilocarpine alginicacid film prepared as follows: first, pilocarpine-free base is dissolvedin freshly prepared deionized water. To this is added a stoichiometricamount of alginic acid and the mixture stirred until a viscous,homogenous solution is obtained. An excess of pilocarpine is then addedand the solution cast onto a glass plate, doctor-bladed to the desiredthickness and dried at room temperature. The transparent elastic andflexible film can be easily peeled off the glass and handled as needed.Films having an alginic acid to pilocarpine ratio of 1 to 12 areprepared, punched to fit inside the reservoir, and then the secondbarrier film laminated to the assembly.

EXAMPLE 4

An ocular insert consisting of a pre-punched colored ethylene-vinylacetate film with an inwardly disposed hole, a pilocarpinepolysaccharide film punched to fit inside the hole and two films placedon the platten in a laminator machine. The machine is closed and avacuum equivalent to 29 inches of Hg is held for 3 minutes. At the endof 3 minutes, a radient heater is turned on and allowed to warm up for15 seconds. The heater is then positioned between the plattens and thesurface of the film heated to 70°C. The heater is then removed and theplattens are pushed together, with approximately 30 pounds of force. Theplattens remain together under pressure of 30 pounds for 45 secondswhile the film cools. The vacuum is then released and the plattensreturned to their original position. Then, the machine is opened, thepilocarpine polysaccharide solid film deposited in the cavity and theremaining clear ethylene-vinyl acetate film placed over the exposedsurface of the second wall. The three walls are returned to thelaminator and the process repeated to yield the finished laminate.

EXAMPLE 5

The procedure of Example 4 is repeated in this example with allconditions as described except the polysaccharide gellation agent isreplaced with the following polysaccharide filmation agents: agar,agarose, kappa-carrageenan and hypnean.

EXAMPLE 6

Following the procedure set forth in Example 1, an ocular drug deliverydevice shaped like a circle 6 mm × 2.5 mm is prepared according to thedescribed procedure, except one of the drug delivery walls is formedfrom commercially available nylon-66, the dye is FDA approved red, andthe drug in the reservoir is hydrocortisone alcohol. The area of thedevice is 1 cm² and the walls are 2 mils thick with the drug releaserate for the ethylene-vinyl acetate copolymer wall about 40 microgramsper hour and the drug release rate for the nylon wall about 2 microgramsper hour.

EXAMPLE 7

Following the procedure set forth in Examples 1 and 2, an ocular drugdelivery device is prepared wherein one drug release rate wall iscellulose acetate, the middle wall is ethylene-vinyl acetate copolymerand is dye-free, and the other drug release rate wall is siliconerubber. The drug release rate for hydrocortisone alcohol through a 1 cm²area wall that is 2 mils thick, is 3 micrograms per hour for thecellulose acetate wall, and 200 micrograms per hour for the siliconerubber drug release rate wall.

EXAMPLE 8

An ocular drug delivery device of banana shape, 21 mm × 5 mm × 0.25 mm,for administering a drug to the eye over prolonged periods of time at acontrolled and continuous drug metered rate, is prepared as follows: adrug-carrier mix is first prepared by mixing liquid polydimethylsiloxanewith 2000 micrograms of hydrocortisone alcohol and stannous octoatecatalyst, 0.5% by weight, with the mixture charged into a preshapedbanana mold having dimensions that correspond to the reservoir area ofan ocular drug delivery device. The drug-steroid carrier is allowed tocure at room temperature and then removed from the mold. Next, thedrug-steroid carrier is placed into the reservoir area of an oculardevice that is comprised of a drug release rate controlling celluloseacetate wall having bonded onto its internal surface an ethylene-vinylacetate banana shaped ring. Then, a second cellulose acetate releaserate wall is heat sealed under vacuum and pressed onto the exposedsurface of the ethylene-vinyl acetate ring to yield the ocular drugdelivery device. The drug delivery walls are characterized by a porosityof 60%, a pore size of 0.45 micron and a thickness of 4 mils. When thedevice is inserted in the cul-de-sac of the conjunctiva between thesclera of the eyeball and the lower lid, the device delivers steroid ata controlled and therapeutically effective rate of drug to the eye for24 hours of treatment.

EXAMPLE 9

A drug delivery device for the administration of a drug to the eye ismanufactured in a rectangular shape by laminating according to theprocedure of Example 1. The device is made by laminating to the outermarginal area of an inner ethylene-vinyl acetate wall having a space inits central area, two outer walls wherein one wall consists of cellulosebutyrate and the other wall poly(propylene) to define between the twoouter walls and interior drug holding space for containing apharmaceutical composition comprised of a drug and a drug carrier.

EXAMPLE 10

A device for releasing chloroamphenicol to the eye at a controlled rateis prepared as follows: first an elliptical ring 5 mm by 8 mm by 8-9mils thick is punched-out from ethylene-vinyl acetate copolymer marketedas Elvax 40 by DuPont. This ring is laminated to a sheet of 3 mil Elvax40 to form an open-topped container. Into this container is placed about8 microliters of a suspension of 25% solid chloramphenicol in asaturated solution in polyethylene glycol. A second sheet of 3 mil Elvax40 is laminated on top to close the container. The ocular insert whenplaced in an eye, releases 20 micrograms/hour of chloroamphenicol.

Thus, the novel ocular drug delivery device of this invention employs aunique means which facilitates the obtainment of precisely controlleddrug release rates. While there have been described and pointed out thefundamental novel features of the invention as applied to the preferredembodiment, those skilled in the art will appreciate that variousmodifications, changes and omissions in the ocular drug delivery deviceillustrated and described can be made without departing from the spiritof the invention.

What is claimed:
 1. An ocular delivery device for the continuousadministration of drug over a prolonged period of time comprising asealed container shaped for insertion into the eye, the container havinga pair of first and third membrane walls spaced from each other, eachformed of a material insoluble in tear fluid, with at least one of themembrane walls being permeable to the passage of drug by diffusion at acontrolled rate, and a second ring-shaped wall interposed between andsealingly engaging the first and third membrane walls along their outerfaced peripheries to define an integral unit and form a reservoirdefined by the inner surfaces of the first, second and third walls, saidreservoir containing drug which is released therefrom at a controlledrate by passage through the rate controlling membrane wall.
 2. An oculardrug dispensing device in accordance with claim 1 wherein said one wallthat is permeable to the drug by diffusion at a predetermined rate isformed of a substantially homogenous and substantially imperforatepolymeric material.
 3. An ocular drug dispensing device in accordancewith claim 1 wherein the first and third walls are both permeable to thedrug by diffusion at a predetermined rate.
 4. An ocular drug dispensingdevice in accordance with claim 1 wherein said one wall that ispermeable to the drug at a predetermined rate is formed of a microporouspolymeric material, the pores of which contain a medium in which thedrug has limited solubility and which is permeable to the drug at thepredetermined rate.
 5. An ocular drug dispensing device in accordancewith claim 1 wherein the second wall is formed of a cold settingadhesive, polymeric material.
 6. An ocular drug dispensing device inaccordance with claim 1 wherein the second wall is formed of a hotsetting adhesive, polymeric material.
 7. An ocular drug dispensingdevice in accordance with claim 1 wherein the second wall has a dyeincorporated in it which makes its color distinct from the colors of thefirst and third walls.
 8. An ocular drug dispensing device in accordancewith claim 1 wherein the first and third walls are formed ofethylene-vinyl acetate copolymer.
 9. An ocular device for the continuousadministration of drug at a controlled rate over a prolonged period oftime comprising a three-layered laminate having a pair of separate anddiscrete first and third walls formed of a material insoluble in tearfluid with at least one of the walls drug release rate controlling andpermeable to the passage of drug by diffusion, a second wall interposedbetween the first and third walls and formed with an inwardly disposedhole with the second wall sealingly engaging the first and third wallsto form a reservoir containing a drug, and wherein drug is administeredfrom the device at a controlled rate by passage through the ratecontrolling wall.
 10. An ocular device for the continuous administrationof drug at a controlled rate for a prolonged period of time according toclaim 9 wherein both the first and third walls are formed of ahomogenous release rate controlling material permeable to the passage ofdrug by diffusion.
 11. An ocular device for the continuousadministration of drug at a controlled rate for a prolonged period oftime according to claim 9 wherein the first wall is formed of ahomogenous material permeable to the passage of drug and the third wallis formed of a material substantially impermeable to drug.
 12. An oculardevice for the continuous administration of drug at a controlled ratefor a prolonged period of time according to claim 9 wherein the secondwall interbonds the first and third walls around their faced marginswith the second wall formed of a flexible, substantially imperforatematerial insoluble in tear fluid.
 13. An ocular device for thecontinuous administration of drug at a controlled rate for a prolongedperiod of time according to claim 9 wherein the reservoir contains acomposition comprising a drug and a carrier which carrier is morepermeable to drug than is the rate-controlling wall.
 14. An oculardevice for the continuous administration of drug at a controlled ratefor a prolonged period of time according to claim 9 wherein the deviceis shaped and sized for insertion and comfortable placement in thecul-de-sac of the eye.
 15. An ocular device for the continuousadministration of drug at a controlled rate for a prolonged period oftime according to claim 9 wherein the rate-controlling walls are formedof ethylene-vinyl acetate copolymer.
 16. An ocular device for thecontinuous administration of drug at a controlled rate for a prolongedperiod of time according to claim 9 wherein the reservoir contains asolid or gel composition comprising a drug and carrier shaped and sizedto correspond to the dimensions of the reservoir.
 17. An ocular devicefor the continuous administration of drug at a controlled rate for aprolonged period of time according to claim 16 wherein the carrier is agellation agent.
 18. An ocular device for the continuous administrationof drug at a controlled rate for a prolonged period of time according toclaim 17 wherein the agent is a polysaccharide.
 19. An ocular device forthe continuous administration of drug at a controlled rate for aprolonged period of time according to claim 9 wherein the reservoircontains alginic acid.
 20. An ocular device for the continuousadministration of drug at a controlled rate for a prolonged period oftime according to claim 19 wherein the reservoir also containspilocarpine and the ratio of pilocarpine to alginic acid is from 12to
 1. 21. A process for making a drug delivery device for dispensingdrug at a predetermined rate for a prolonged period of timecomprising:a. forming a first wall from a material insoluble in tearfluid and optionally permeable to drug at a predetermined rate; b.forming a second wall from a material insoluble in tear fluid in a ringshape having an outer perimeter of generally the same shape as theperimeter of the first wall; c. placing the second wall on the firstwall with the outer perimeter of the second wall in general registrywith the perimeter of the first wall; d. charging drug onto the surfaceof the first wall in the reservoir area thereof bounded by the innerperimeter of the second wall; e. forming a third wall from a materialinsoluble in eye fluid and optionally permeable to drug at apredetermined rate, with the proviso that at least one of the first andthird walls is permeable to drug at a predetermined rate, in the samegeneral shape as the first wall; f. placing the third wall over the drugwith its perimeter in general registry with the outer perimeter of thesecond wall and its periphery contacting said second wall; and g.sealing the first and third walls to the second wall.
 22. A process inaccordance with claim 21 wherein the first and third walls are heatsealed to the second wall.
 23. A process in accordance with claim 21wherein the second wall is formed of a cold setting adhesive polymericmaterial and the first and third walls are heat sealed to the secondwall at 5°C to 50°C.
 24. A process in accordance with claim 21 whereinthe second wall is formed of a hot setting adhesive polymeric materialand the first and third walls are heat sealed to the second wall at 50°Cto 250°C.
 25. A process in accordance with claim 21 wherein the firstand second walls are formed from polymeric materials permeable to thedrug at different, predetermined rates.
 26. A process in accordance withclaim 21 wherein the second wall is of a color which distinguishes itfrom the first and third walls.
 27. A process in accordance with claim21 wherein the drug delivery device is an ocular device in a shape andsize adapted for insertion in a cul-de-sac of the eye.
 28. A process inaccordance with claim 21 wherein the drug is initially of a liquidcharacter and is reacted or mixed with a gelling agent to form a gelledcomposition prior to charging the formulation onto the surface of thefirst wall in step (d) of said process.
 29. A process in accordance withclaim 28 wherein the gellation agent is agar, alginic acid, carrageenan,laminaran, tragacanth, gum arabic or gum ghatti.
 30. A process inaccordance with claim 28 wherein the drug is pilocarpine and the gellingagent is alginic acid.